Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation
Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation
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组成型雄甾烷受体的激活可防止胆固醇胆结石形成
DOI：
10.1016/j.ajpath.2016.12.013
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发表时间：
2017-04-01
影响因子：
6
通讯作者：
He, Jinhan
中科院分区：
文献类型：
--
作者：
Cheng, Shihai;Zou, Min;He, Jinhan
胆固醇结石病（Cholesterol gallstone disease，CGD）是最常见的胃肠道疾病之一。致石性肝胆汁分泌先于胆固醇结石形成。组成型雄烷受体（CAR）是细胞核家族成员，在胆固醇和胆汁酸代谢中起重要作用。为了检查CAR的激活是否可以防止胆固醇结石形成，我们用CAR激动剂1，4-双-[2-（3，5-二氯吡啶氧基）]苯处理维持致石饮食的C57 BL 6/J小鼠，并进行胆管插管以研究胆汁脂质的动力学。我们报道CAR的激活降低胆汁胆固醇浓度并防止CGD形成。较低的胆汁胆固醇水平在很大程度上归因于CAR活化小鼠中Abcg 5和Abcg 8表达的抑制。CAR激活还通过增加Cyp 7a 1（胆汁酸生物合成中的限速酶）的表达来促进胆固醇转化为胆汁酸。CAR的激活通过增加回肠中胆汁酸转运蛋白Asbt和Ost β的表达来增强胆汁酸重吸收。在CAR活化的小鼠的肝脏中，肝脏脂肪变性也得到改善。此外，CAR的活化通过抑制Abcg 5/8的表达来保护小鼠免受肝脏X受体α致敏的CGD。总体而言，CAR在维持胆固醇、胆汁酸和甘油三酯水平的稳态中起重要作用，并且其可能是预防或治疗CGD的有希望的治疗靶点。
Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichiorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol Level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and 0st beta in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the Liver X receptor alpha-sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.